Contributions
Abstract: S811
Type: Oral Presentation
Presentation during EHA22: On Sunday, June 25, 2017 from 08:30 - 08:45
Location: Room N109
Background
Congenital Dyserythropoietic Anemias (CDAs) are subtypes of bone marrow failure syndromes, hallmarked by ineffective erythropoiesis. The most common form is CDAtype II (CDAII), showing moderate/severe anemia, relative reticulocytopenia, jaundice, and iron overload. It is inherited as autosomal recessive disorderdue to loss-of-function mutations inSEC23B gene. More than 300 CDAII cases and 80 causative mutationshave been described so far. Despite this high allelic heterogeneity, two variants, R14W and E109K, represent more than 50% of the mutational events. To date, treatments for CDAII patients consist of supportive therapy, such as erythrocyte transfusions, or bone marrow transplantation or splenectomy in transfusion-dependentcases.Recently, members of TGF-β superfamily have been studied as potential regulators of erythropoiesis,especially the growth differentiation factor 11 (GDF11). Through the binding of specific receptors, GDF11 leads to an inhibited late-stage erythropoiesis. Indeed, two GDF11 inhibitors, ACE-011 and ACE-536,have been associated to an improvement of hematologic parameters. Studies with the mouse counterpart of ACE-011, RAP-011, on mouse model of β-thalassemia showed increased differentiation of erythroid cells, improvement of anemic condition and reduced iron overload in treated mice.
Aims
The main aim of our study is to assess the effects of RAP-011 on different cellular models of CDAII.
Methods
We measured circulating GDF11 levels in CDAII patients and healthy controls(HC) bywestern blot(WB). To assess the effectiveness of RAP-011(provided by Celgene Corporation)in vitro, we established two different cellular models of CDAII: (i) K562 cells stably silencedfor SEC23B by Sh-RNA carried in GIPZ lentiviral vectors; (ii) K562 stably overexpressing SEC23B-WT and the two variants, R14W and E109K. In vitro treatment has been performed at 0, 3, and 6 days of erythroid differentiation by hemin + GDF11 in presence or absence of RAP-011 in K562 cells stably silencedfor SEC23B.
Results
Conclusion
Session topic: 31. Other Non-malignant hematopoietic disorders
Keyword(s): Treatment, Bone Marrow Failure, Anemia
Abstract: S811
Type: Oral Presentation
Presentation during EHA22: On Sunday, June 25, 2017 from 08:30 - 08:45
Location: Room N109
Background
Congenital Dyserythropoietic Anemias (CDAs) are subtypes of bone marrow failure syndromes, hallmarked by ineffective erythropoiesis. The most common form is CDAtype II (CDAII), showing moderate/severe anemia, relative reticulocytopenia, jaundice, and iron overload. It is inherited as autosomal recessive disorderdue to loss-of-function mutations inSEC23B gene. More than 300 CDAII cases and 80 causative mutationshave been described so far. Despite this high allelic heterogeneity, two variants, R14W and E109K, represent more than 50% of the mutational events. To date, treatments for CDAII patients consist of supportive therapy, such as erythrocyte transfusions, or bone marrow transplantation or splenectomy in transfusion-dependentcases.Recently, members of TGF-β superfamily have been studied as potential regulators of erythropoiesis,especially the growth differentiation factor 11 (GDF11). Through the binding of specific receptors, GDF11 leads to an inhibited late-stage erythropoiesis. Indeed, two GDF11 inhibitors, ACE-011 and ACE-536,have been associated to an improvement of hematologic parameters. Studies with the mouse counterpart of ACE-011, RAP-011, on mouse model of β-thalassemia showed increased differentiation of erythroid cells, improvement of anemic condition and reduced iron overload in treated mice.
Aims
The main aim of our study is to assess the effects of RAP-011 on different cellular models of CDAII.
Methods
We measured circulating GDF11 levels in CDAII patients and healthy controls(HC) bywestern blot(WB). To assess the effectiveness of RAP-011(provided by Celgene Corporation)in vitro, we established two different cellular models of CDAII: (i) K562 cells stably silencedfor SEC23B by Sh-RNA carried in GIPZ lentiviral vectors; (ii) K562 stably overexpressing SEC23B-WT and the two variants, R14W and E109K. In vitro treatment has been performed at 0, 3, and 6 days of erythroid differentiation by hemin + GDF11 in presence or absence of RAP-011 in K562 cells stably silencedfor SEC23B.
Results
Conclusion
Session topic: 31. Other Non-malignant hematopoietic disorders
Keyword(s): Treatment, Bone Marrow Failure, Anemia